PROJECT SUMMARY/ABSTRACT For most of the last century, it was thought that all epigenetic information in germ cells was erased at the start of each new generation. However, it is now known that this is not always the case. Many examples of epigenetic information escaping reprogramming and crossing generational boundaries have now been documented (collectively termed transgenerational epigenetic inheritance or TEI). Examples of TEI include paramutation in plants, RNAi inheritance in C. elegans, and the inheritance of acquired traits in mice. Given the large number of cases of TEI that have now been observed, it is possible that TEI may be an important adaptive process with significant implications for our understanding of heredity. We do not yet understand how epigenetic information is inherited, how TEI is regulated, or why animals possess TEI systems. One dramatic example of TEI occurs in the model organism C. elegans: in C. elegans, the effects of double stranded (ds)RNA exposure (termed RNA interference, RNAi) can be passed from parent to progeny for more than five generations (termed RNAi inheritance). I hypothesized that C. elegans possess systems that limit TEI inheritance and by removing these limiting systems, TEI might last for more generations than usual. With this idea in mind, I performed a forward genetic screen to identify mutations that make RNAi inheritance last for more generations than normal. My screen identified the gene heritable enhancer of RNAi 1 (heri-1). heri-1 encodes a gene whose protein product contains two conserved domains: a putative chromodomain and a domain with homology to kinases. I have found that HERI-1 is recruited to genomic sites targeted by RNAi and the recruitment of HERI-1 to these sites limits the inheritance of epigenetic information at these sites. As far as I am aware, HERI-1 represents the first known factor dedicated to the regulation of TEI in animals. The research strategy proposed here is designed to provide further insights into how epigenetic inheritance is regulated. There is currently intense scientific debate about whether or not epigenetic information can be inherited in humans and whether or not inherited epigenetic information might contribute to human disease. If the answer to this question turns out to be yes, my work exploring how TEI is regulated could help us understand the basic molecular mechanisms that limit and regulate epigenetic inheritance and, thus, make it possible to influence heritable epigenetic processes in such a way as to mitigate human disease.